Inhibitory Effects of Protein Kinase C on Inwardly Rectifying K + - and ATP-Sensitive K + Channel-Mediated Responses of the Basilar Artery

Abstract

Background and Purpose — The structurally related, inwardly rectifying K + (K IR ) channel and the ATP-sensitive K + (K ATP ) channel are important modulators of cerebral artery tone. Although protein kinase C (PKC) activators have been shown to inhibit these channels with the use of patch-clamp electrophysiology, effects of PKC on K + channel function in intact cerebral blood vessels are unknown. We therefore tested whether pharmacological alteration of PKC activity affects cerebral vasodilator responses to K IR and/or K ATP channel activators in vivo. Methods — We measured changes in basilar artery diameter using a cranial window preparation in anesthetized rats. In addition, intracellular recordings of smooth muscle membrane potential were made in isolated basilar arteries. Results — K + (5 to 15 mmol/L) and aprikalim (1 to 10 μmol/L) each elicited reproducible vasodilatation. The PKC activator phorbol-12,13-dibutyrate (PdBu) (50 nmol/L) inhibited responses to K + (by 40% to 55%) and aprikalim (by 40% to 70%), whereas responses to papaverine were unaffected. The PKC inhibitor calphostin C (0.1 μmol/L) augmented responses to K + (by 2- to 3-fold) and aprikalim (2-fold) but not papaverine. In addition, K + (5 mmol/L) and aprikalim (3 μmol/L) each hyperpolarized the basilar artery. PdBu inhibited these responses to aprikalim by 45% but had no effect on K + -induced hyperpolarization. Conclusions — These data suggest that both basal and stimulated PKC activity inhibit K IR and K ATP channel–mediated cerebral vasodilatation in vivo. The inhibitory effect on K ATP channel–mediated vasodilatation occurs at least partly by inhibition of hyperpolarization mediated by K ATP channels. PKC inhibits K + -induced vasodilatation without affecting hyperpolarization, suggesting that the inhibitory effect of PKC on vasodilator responses to K + does not involve altered K IR channel function.